The treatment of eye diseases by injecting a therapeutic agent directly in the vitreous chamber has shown promising results in the past. Macugen® (oligonucleotide) and Lucentis® (monoclonal antibody) are pharmaceutical products which are efficient to treat retinal diseases.
However, their half-life in the vitreous is relatively short, leading to repeated injections to maintain the effect. The rapid clearance of these products is due to the renewal of the vitreous liquid over time.
This issue was already addressed in the prior art: for example, WO2009/046198 describes a method for administering a therapeutic agent in the vitreous with a sustained release kinetic; this method involves the formation of a macroscopic gel-like structure comprising said therapeutic agent, in the vitreous chamber. Also, EP2187980 describes the injection in the vitreous chamber of a therapeutic agent combined with a polymeric precursor, which will form in situ a hydrogel suitable for controlled release of said therapeutic agent.
However, the injection in the vitreous of a subject of a gel or gel-like structure as described in these patent applications may cause visual discomfort to the subject due to the invasion of the visual field by said gel or gel-like structure.
In further prior art documents, a solid implant may be injected in the eye of the subject for release of the active ingredient over several months. However, this form of administration introduces a solid body within the eye of the patient, which in some cases is not wished. Moreover, this approach is more adapted for administration of lipophilic agents than for administration of hydrophilic agents, and may not be selected for administration of biological agents such as proteins and monoclonal antibodies.
Therefore, there remains a need for a method for sustaineously releasing in the vitreous chamber, a composition comprising a hydrophilic therapeutic agent, such as for example a protein or a nucleic acid. Ensuring the visual comfort of the patient when the composition is within the vitreous body is another issue.
Surprisingly, the Applicant realized that a water-in-oil emulsion could be an efficient vehicle for administering hydrophilic therapeutic agents. Water-in-oil type emulsions are biphasic systems in which water droplets are dispersed within an oil phase.
The use of water-in-oil type emulsions as vehicles for sustained release of therapeutic agents is well known in the art. For example, WO01/89479 discloses the use of water-in-oil type emulsions for the parenteral administration of hydrophilic active ingredients with a sustained release kinetic.
This invention thus relates to the use of water-in-oil type emulsions for intraocular administration of a therapeutic agent to a subject in need thereof, providing a sustained release kinetic, and avoiding any invasion of the field of vision of the subject in his/her everyday life or safety issues.
An advantage of the solution proposed by the Applicant is that when injected intraocularly, the water-in-oil emulsion of the invention forms a reservoir of therapeutic agent that may be in the form of a layer or in the form of a bubble, having a lower density than the vitreous liquid. Therefore, when injected, the composition will rapidly (within 0.5 seconds to 1 minute) shift up from injection location to the upper part of the vitreous. Consequently, this liquid reservoir will float over the vitreous, out of the visual field, avoiding any visual discomfort for the subject to which the composition is administered. The therapeutic agent is then sustaineously released from the reservoir over a period of time ranging from two weeks to 6 months. The composition of the invention has the further advantage of being in physical contact with both vitreous body and targeted tissues such as, for example, the choroid or the retina, resulting in a targeted release of the therapeutic agent.